Astrocytes are the most abundant cells in the central nervous system, however their role in health and disease remains a mystery. Astrocytes are very heterogeneous in structure and molecular profile. A single astrocyte creates a distinct non-overlapping territory that encompasses thousands of synapses. Their extensive branches and fine processes allow direct communication over long distances, as well as indirect communication through secretion of chemokines and cytokines. Astrocytes are also a significant component of the neurovascular unit as their endfeet processes terminate directly onto cerebral vessels, regulating cerebral blood flow according to metabolic demand. While in vitro models, including primary astrocytes and acute brain slices, have provided great insight into the physiology of astrocytes in health and disease scenarios, it is clear these preparations devoid of the complexity of the role of astrocytes in vivo. Thus, efforts to study astrocyte physiology should be directed as much as possible to the most physiologically relevant system: the intact living brain. We and others have demonstrated through in vivo imaging of intracellular calcium that astrocytes are dynamic players in the brain, and that the progression of Alzheimer's disease pathology alters their morphology and signaling characteristics. More specifically, we determined that in the presence of senile plaques, astrocytes in the brain have elevated intracellular calcium, exhibit hyperactive signaling, and can initiate spontaneous calcium waves. This allows astrocytes to respond to focal pathological insults with both focal and long range responses. These observations demonstrated that astrocytes respond to amyloid deposition with a change in function, but left several fundamental questions unanswered. Here, we wish to extend our previous observations and determine what the contribution of the altered calcium signaling is to the degenerative process that occurs in AD. The use of genetically encoded indicators, specifically expressed in astrocytes, along with in-vivo imaging will allow us to explore the effect of amyloid on astrocyte structure and function at the synapse and the neurovascular unit. We will also determine if the alterations depend on senile plaque deposition, or soluble oligomeric A? and whether the alterations are beneficial or detrimental to brain function. We propose experiments where astrocyte specific increases or decreases in calcium signaling will be evaluated in healthy and diseased brains. Finally, we will ask how clinically relevant manipulation of the amyloid cascade will affect calcium signaling in astrocytes and the degenerative process. These experiments will shed light on the role of astrocytes in the healthy and diseased brain, and will lead to new targets for therapeutic manipulation in Alzheimer's disease.